N-Aralkyl substitution increases the affinity of adrenergic drugs for the alpha-adrenoceptor in rat liver.

1 The alpha-adrenoceptor of rat liver plasma membranes was studied by use of the specific alpha-antagonist [3H]-dihydroergocryptine ([3H]-DHEC). Catecholamines and adrenergic compounds displayed an order of affinity that is typical of an alpha-receptor. Nevertheless, protokylol, a potent beta-adrenoceptor agonist, exhibited a higher affinity than that of adrenaline for alpha-sites. This result might be due to its bulky substituent on the amino group. 2 Further displacement experiments between [3H]-DHEC and four pairs of drugs differently substituted on the amino group (isoprenaline vs Cc-25, orciprenaline vs fenoterol, AH 3474 vs labetalol, pindolol vs hydroxybenzylpindolol) provided evidence that N-alkyl substitution decreased the affinity for alpha-sites (20 micromolar less than KD less than 200 micromolar), whereas an N-aralkyl one increased the affinity (0.17 micromloar less than KD less than 4.6 micromolar). 3 It is concluded that a substitution on the amino group by a bulky, hydrophobic moiety enhances the affinity of drugs for the alpha-adrenoceptors.